Apolipoprotein A-I (apoA-l) and HDL are both inversely correlated with the onset of premature cardiovascular disease. Current screening guidelines established by the NCEP suggest measuring HDL cholesterol on all patients being evaluated for risk of cardiovascular disease. Not all individuals with low HDL are at risk for coronary artery disease. Some individuals with genetic causes of low levels of HDL are not at risk of significant premature atherosclerosis such as LCAT deficiency, Fish Eye disease, and Tangier disease. Other disorders with low HDL such as apoA-l deficiency are at risk for developing premature cardiovascular disease. We have investigated several kindreds with these disorders to investigate the mechanisms involved in the development of or protection from early atherosclerosis. ApoA-l and apoA-ll are the two major apolipoproteins involved in HDL catabolism. ApoA-l is found on HDL particles containing only apoA-l (LpA-l) and on particles containing apoA-l and apoA-ll (LpA- l:A-II). Several lines of evidence suggests that LpA-l not LpAI:AII is the protective lipoprotein particle in HDL. To investigate the role of apoA-I and apoA-II in vivo in humans, metabolic studies using radiolabeled apoA and apoA-II were done to investigate the role of each apolipoprotein in HDL metabolism. Kinetic studies in patients with LCAT deficiency were shown to have faster catabolism of apoA-l on LpA-1:A-II particles than apoA-I on LpA-I particles resulting in a selective proportional decrease in the plasma levels of LpA-I:A-II and a sparing effect on the reduction of LpA-I levels. Five kindreds with familial hypoalphalipoproteinemia who have no cardiovascular disease have also been studied. Both LpA-I and LpA-I:A-II were rapidly catabolized but LpA-I:A-II is slightly faster than LpA-I resulting in a normal or increased ratio of LpA-I/LpA-I:A-II. To further investigate the role of apoA-I and apoA-lI in HDL metabolism, we have studies a 26 year old patient with apoA-I deficiency and a HDL of 9 mg/dl. The patient had cutaneous xanthomas and early atherosclerosis was evident based on calcification seen on an ultrafast CT scan. We performed in vivo kinetic studies of apoA-II in the patient and in controls. Preliminary results suggest that the catabolism of apoA-Il was markedly enhanced in the patient with apoA-I deficiency. This suggests that in the absence of apoA-l, apoA-II is metabolized very quickly and does not confer a protective role. Additional studies will help us understand the role of apoA-lI in the development of premature cardiovascular disease.